1. Field of the Invention
The present invention relates to a new synthetic material apt to stably adsorb high quantities of heparin. Said material is therefore particularly suited for manufacturing protheses or other medical equipment, to which it confers remarkable non-thrombogenic properties when placed in contact with blood.
The invention also concerns a preferred process for the production of the aforementioned material, and the use of such material in manufacturing protheses and other medical equipment designed to come in contact with blood.
It is known that blood, in contact with the surface of prosthetic elements, generally determines the formation of blood clots. This at present constitutes the most serious factor limiting the use of synthetic materials (and particularly polymeric materials) in the field of protheses and artificial organs. The formation of blood clots may be chemically avoided by the systemic administration of anti-coagulants. The inadequacy of such a step is evident in the case of protheses designed to remain permanently in the organism, since, in this case, the entire circulatory system of the patient must be maintained in a modified condition, often for life. The above perhaps constitutes the main reason whereby it has not yet been possible to introduce an artificial heart in medical practice.
2. Description of the Prior Art
In order to reduce blood clot formation caused by polymeric material, a number of methods have been suggested; among these, the superficial heparinization of the above materials is undoubtedly one of the most important. Heparin is in fact endowed with marked anti-coagulant properties and is commonly used, in aqueous solution, as an anti-coagulant. It consists of a high charge-density acid mucopolysaccharide containing sulphonic, sulphamic and carboxylic groups. The aqueous solution behaves like a strong acid, and at a physiological pH, the substance is completely ionized. As mentioned above, it is known that heparin, bonded or in any case adsorbed by any type of material, is apt to confer to this latter non-thrombogenic properties.
The U.S. Pat. No. 3.865.723 hence describes basic polymers, obtained by polyaddition of bis-acrylamides with secondary diamines, apt to form stable complexes with heparin, but having mechanical properties of high rigidity and scarce moldability, which make them in practice unsuitable for use in the biomedical field.
Other similar polymeric materials have been described in Experientia 1973, 29, 93; Polymer 1977, 18, 378; J. Polym. Science 1977, 15, 2151; Polymer 1978, 19, 1063; Biomaterials 1983, 4, 218; Italian Patent application No. 20968 A/84 filed on May 17, 1984.
Of particular interest are polymers based on poly(amidoamine)s (PAA), which are apt to form stable complexes with heparin in an aqueous medium; such a property is maintained also when the PAA are inserted as segments in block copolymers with other types of polymers--e.g. polyethylene and polystyrene--or are grafted onto the surface of various materials, as glass, Dacron, etc.
Recent studies have finally been made on the possibility of associating PAA with polyurethanes. Said association in fact appears to be particularly advantageous, as it would allow to combine the easy heparinization properties of PAA with the satisfactory mechanical characteristics of polyurethanes, which have placed these materials among those most frequently used as components for equipment designed to come in contact with blood; e.g. vascular protheses, blood filters, catheters, cardiac valves, etc.
A first proposed method for obtaining said association consists in reacting first macrodiols with an excess of diisocyanate, thereby obtaining a polyurethane with reactive diisocyanate branches, onto which the PAA are subsequently grafted. A second method consists instead in carrying out a chemical etching directly onto a polyurethane prothesis, grafting thereon first the diisocyanate and subsequently the PAA.
Nevertheless, neither of said methods have given satisfactory results. In fact, in the first case, the reaction of copolymerization is not easy to control, whereby the product obtained does not provide sufficiently constant and reproducible chemical-physical characteristics, to allow a practical application thereof. The second method does not have this drawback, but the chemical etching of the grafting onto the polyurethane prosthetic element deteriorates, at times even considerably, its mechanical characteristics. In either case, there is anyhow a relative incompatibility with blood, which is essentially determined by the presence of a still insufficient number of active centres capable of stably bonding heparin.